15-ketal postaglandins for the treatment of glaucoma or ocular hypertension

Abstract

A method of treating glaucoma or ocular hypertension in a patient, which comprises administering to the patient a pharmaceutically effective amount of a compound of formula I:

What is claimed is:  
     
       1. A method of treating glaucoma or ocular hypertension in a patient suffering therfrom, which comprises administering to the patient a pharmaceutically effective amount of a compound of formula I:                    
       wherein: 
       R 1 =CO 2 R, CONR 4 R 5 , CH 2 OR 6 , or CH 2 NR 7 R 8 ; where:  
       R=H or cationic salt moiety, or CO 2 R=ophthalmically acceptable ester moiety; R 4 , R 5 =same or different=H or alkyl; R 6 =H, acyl, or alkyl; R 7 , R 8 =same or different=H, acyl, or alkyl; with the proviso that if one of R 7 , R 8 =acyl, then the other=H or alkyl;  
       n=0 or 2  
       R 2 =H, alkyl, or acyl;  
       R 3 =H, halo, or OR 9 ; where R 9 =H, alkyl, or acyl;  
         - - - - =single or non-cumulated double bond, with the provisos that if a double bond is present between carbons 4 and 5, it is of the cis configuration; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;  
       X=(CH 2 ) m  or (CH 2 ) m O, where m=1-6; and  
       Y=phenyl, optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or  
       X—Y=(CH 2 ) p Y 1 ; where p=0-6; and                    
       wherein: 
       W=CH 2 , O, S(O) q , NR 10 , CH 2 CH 2 , CH═CH, CH 2 O, CH 2 S(O) q , CH═N, or CH 2 NR 9 ; where q=0-2, and R 10 =H, alkyl, or acyl;  
       Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and  
         - - - - =single or double bond;  
       with the proviso that the following compounds are excluded: etiproston and its pharmaceutically acceptable salts and esters.  
     
     
       2. The method of  claim 1 , wherein the compound is administered topically. 
     
     
       3. The method of  claim 2 , wherein the compound is administered as a solution, suspension or emulsion. 
     
     
       4. The method of  claim 1 , wherein: 
       R 1 =CO 2 R, where R=H; or CO 2 R=ophthalmically acceptable ester moiety;  
       R 2 =H;  
       n=0;  
       R 3 =OH in the alpha (α) configuration, or Cl or F in the beta (β) configuration;  
         - - - - =single or non-cumulated double bond, with the provisos that if double bond is present between carbons 4 and 5 or carbons 5 and 6, it is of the cis configuration; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;  
       X=CH 2 O; and  
       Y=phenyl, optionally substituted with halo or trihalomethyl.  
     
     
       5. The method of  claim 2 , wherein the concentration of the compound is between about 0.00003 to about 0.5 weight percent. 
     
     
       6. The method of  claim 5 , wherein the concentration of the compound is between about 0.0005 to about 0.03 weight percent. 
     
     
       7. The method of  claim 6 , wherein the concentration of the compound is between about 0.001 to about 0.01 weight percent. 
     
     
       8. The method of  claim 5 , wherein the compound is:                    
     
     
       9. The method of  claim 5 , wherein the compound is:                    
     
     
       10. The method of  claim 5 , wherein the compound is:                    
     
     
       11. The method of  claim 5 , wherein the compound is:                    
     
     
       12. The method of  claim 5 , wherein the compound is:                    
     
     
       13. The method of  claim 5 , wherein the compound is:                    
     
     
       14. A compound of formula (I):                    
       wherein: 
       R 1 =CO 2 R, CONR 4 R 5 , CH 2 OR 6 , or CH 2 NR 7 R 8 ; where:  
       R=H or cationic salt moiety, or CO 2 R=pharmaceutically acceptable ester moiety; R 4 , R 5 =same or different=H or alkyl; R 6 =H, acyl, or alkyl; R 7 , R 8 =same or different=H, acyl, or alkyl; with the proviso that if one of R 7 , R 8 =acyl, then the other=H or alkyl;  
       n=0 or 2;  
       R 2 =H, alkyl, or acyl;  
       R 3 =H, halo, or OR 9 ; where R 9 =H, alkyl, or acyl;                    
       single or non-cumulated double bond, with the provisos that a cis double bond is present between carbons 4 and 5; and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;  
       X=(CH 2 ) m  or (CH 2 ) m O, where m=1-6; and  
       Y=phenyl, optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or  
       X—Y=(CH 2 ) p Y 1 ; where p=0-6; and                    
       wherein: 
       W=CH 2 , O, S(O) q , NR 10 , CH 2 CH 2 , CH═CH, CH 2 O, CH 2 S(O) q , CH═N, or CH 2 NR 9 , where q=0-2, and R 10 =H, alkyl, or acyl;  
       Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and                    
       single or double bond.  
     
     
       15. The compound of claims  14  wherein: 
       R 1 =CO 2 R; where R=H; or CO 2 R=pharmaceutically acceptable ester moiety, where R=alkyl;  
       n=0;  
       R 2 =H;  
       R 3 =OH in the alpha (α) configuration, or Cl or F in the beta (β) configuration;  
       X=CH 2 O; and  
       Y=phenyl, optionally substituted with halo or trihalomethyl.  
     
     
       16. The compound of  claim 15 , having the formula:                    
     
     
       17. An ophthalmic composition for the treatment of glaucoma and ocular hypertension, comprising a compound of formula I:                    
       wherein: 
       R 1 =CO 2 R, CONR 4 R 5 , CH 2 OR 6 , or CH 2 NR 7 R 8 ; where:  
       R=H or cationic salt moiety, or CO 2 R=ophthalmically acceptable ester moiety; R 4 , R 5 =same or different=H or alkyl; R 6 =H, acyl, or alkyl; R 7 , R 8 =same or different=H, acyl, or alkyl; with the proviso that if one of R 7 , R 8 =acyl, then the other=H or alkyl;  
       n=0 or 2  
       R 2 =H, alkyl, or acyl;  
       R 3 =H, halo, or OR 9 ; where R 9 =H, alkyl, or acyl;  
         - - - - =single or non-cumulated double bond, with the provisos that [if a double bond] a cis double bond is present between carbons 4 and 5, and that if a double bond is present between carbons 13 and 14, it is of the trans configuration;  
       X=(CH 2 ) m  or (CH 2 ) m O, where m=1-6; and  
       Y=phenyl, optionally substituted with alkyl, halo, trihalomethyl, alkoxy, acyl, acyloxy, amino, alkylamino, acylamino, or hydroxy; or  
       X—Y=(CH 2 ) p Y 1 ; where p=0-6; and                    
       wherein: 
       W=CH 2 , O, S(O) q , NR 10 , CH 2 CH 2 , CH═CH, CH 2 O, CH 2 S(O) q , CH═N, or CH 2 NR 9 , where q=0-2, and R 10 =H, alkyl, or acyl;  
       Z=H, alkyl, alkoxy, acyl, acyloxy, halo, trihalomethyl, amino, alkylamino, acylamino, or hydroxy; and  
         - - - - =single or double bond;  
       and an ophthalmically acceptable vehicle therefor.  
     
     
       18. The composition of  claim 17  wherein: 
       R 1 =CO 2 R; where R=H; or CO 2 R=ophthalmically acceptable ester moiety, where R=alkyl;  
       n=0;  
       R 2 =H;  
       R 3 =OH in the alpha (α) configuration, or Cl or F in the beta (β) configuration;  
       X=CH 2 O; and  
       Y=phenyl, optionally substituted with halo or trihalomethyl.  
     
     
       19. The composition of  claim 18 , wherein the compound is of the following formula:                    
     
     
       20. A method of treating glaucoma or ocular hypertension in a patient, which comprises administering to the patient a pharmaceutically effective amount of a composition consisting essentially of isopropyl ester of etiproston and a pharmaceutically acceptable vehicle therefor.